CN115461341A

CN115461341A - Crystalline forms of 2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile

Info

Publication number: CN115461341A
Application number: CN202180010157.0A
Authority: CN
Inventors: P·菲亚松萨; K·拜伊; J·鲍姆
Original assignee: Principia Biopharma Inc
Current assignee: Principia Biopharma Inc
Priority date: 2020-01-22
Filing date: 2021-01-21
Publication date: 2022-12-09
Also published as: CO2022009916A2; WO2021150723A1; JP2023511105A; CA3164698A1; MX2022009009A; BR112022014149A2; US20210221818A1; KR20220130184A; TW202140484A; AU2021209884A1; US11814390B2; EP4093741A1; IL294785A

Abstract

Crystalline forms of compound (I) are disclosed, as are pharmaceutical compositions comprising the crystalline forms of compound (I), methods of using the crystalline forms of compound (I) to treat disorders and conditions mediated by BTK activity, and processes for preparing compound (I) and crystalline forms thereof.

Description

Crystalline forms of 2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile

This application claims priority to U.S. provisional application No. 62/964,378, filed on 22/1/2020, the contents of which are incorporated herein by reference in their entirety.

Disclosed herein are crystalline forms of 2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile (compound (I)), methods of using the crystalline forms of compound (I), and methods of preparing compound (I), including various crystalline forms thereof. The crystalline form of compound (I) is an inhibitor of Bruton's Tyrosine Kinase (BTK). The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases.

BTK is expressed in most hematopoietic cells including B cells, mast cells and macrophages. BTK plays a role in the development and activation of B cells and is implicated in a variety of signaling pathways across a wide range of immune-mediated diseases. BTK activity is implicated in the pathogenesis of several disorders and conditions, such as B cell-associated hematological cancers (e.g., non-hodgkin's lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, sjogren's syndrome, pemphigus, inflammatory bowel disease, lupus and asthma).

Compound (I) may inhibit BTK and may be useful for treating disorders and conditions mediated by BTK activity. Compound (I) is disclosed in example 31 of WO 2014/039899 and has the following structure:

wherein C is a stereochemical center. An alternative procedure to produce compound (I) is described in example 1 of WO 2015/127310.

Solid forms (e.g., crystalline forms) of biologically active compounds, such as compound (I), are of interest in the pharmaceutical industry, where a solid form having particular physical, chemical, or pharmaceutical properties, such as solubility, dissociation, true density, dissolution, melting point, morphology, compaction behavior, particle size, flow characteristics, or solid state stability, may be desirable or even required for drug development. When substances of the same composition crystallize in different lattice arrangements, crystal forms form, resulting in different thermodynamic properties and stabilities characteristic of each crystal form. Each unique crystal form is called a "polymorph" (polymorph).

Although polymorphs of a given substance have the same chemical composition, they may differ from each other in at least one physical, chemical and/or pharmaceutical property (e.g., solubility, dissociation, true density, dissolution, melting point, crystal habit or morphology, compaction behavior, particle size, flow characteristics and/or solid state stability). The solid state form of a biologically active compound generally dictates its ease of preparation, ease of isolation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids, and in vivo bioavailability.

There is currently no way to predict the likely solid forms (e.g., crystalline forms) of a compound, whether any such form would be suitable for commercial use in a pharmaceutical composition, or which form or forms would exhibit the desired properties. Because different solid forms (e.g., crystalline forms) can have different properties, reproducible methods for producing substantially pure solid forms are also desirable for biologically active compounds intended for use as pharmaceuticals.

Thus, there is a need for novel solid forms (including novel crystalline forms thereof), such as compound (I), useful in the treatment of disorders and conditions mediated by BTK activity, and reproducible, scalable methods of making the novel solid forms.

Disclosed herein are novel crystalline forms of compound (I), compositions comprising the novel crystalline forms of compound (I), and methods of using and making the novel crystalline forms of compound (I). In some embodiments, the novel crystalline forms disclosed herein have properties useful for large scale manufacturing, pharmaceutical formulation, and/or storage. In some embodiments, the novel crystalline forms disclosed herein consist of one crystalline form. In some embodiments, the crystalline form is substantially pure.

Some embodiments of the present disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable excipient; and at least one crystalline form selected from crystalline forms of compound (I). In some embodiments, the at least one crystalline form is form a of compound (I). In some embodiments, the at least one crystalline form is form B of compound (I). In some embodiments, the at least one crystalline form is form C of compound (I).

Some embodiments of the present disclosure relate to methods of inhibiting BTK in a mammal by administering to a mammal in need of such BTK inhibition a therapeutically effective amount of at least one crystalline form selected from crystalline forms of compound (I). In some embodiments, the at least one crystalline form is form a of compound (I). In some embodiments, the at least one crystalline form is form B of compound (I). In some embodiments, the at least one crystalline form is form C of compound (I).

In some embodiments, a mammal in need of BTK inhibition has a disease mediated by BTK. In some embodiments, the BTK-mediated disease is selected from: <xnotran> , , , , , , , , , , , - , TEN , , , , (leucoclastic vasculitis), , , , , , (sweet syndrome), , , , , , , , , , , , (Wegener' sgranulomatosis), , , , , , , , B , , , , B , / (Waldenstrom macroglobulinemia), , , , B , B , , () B , , B , , / . </xnotran>

In some embodiments, the disease mediated by BTK is pemphigus vulgaris. In some embodiments, the disease mediated by BTK is pemphigus foliaceus. In some embodiments, the disease mediated by BTK is immune thrombocytopenia. In some embodiments, the disease mediated by BTK is lupus nephritis.

In some embodiments, the mammal in need of BTK inhibition is a human. In some embodiments, the mammal in need of BTK inhibition is a canine.

The present invention also discloses a process for preparing at least one crystalline form selected from the crystalline forms of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is form a of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is form B of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is form C of compound (I).

Drawings

Figure 1 shows an X-ray powder diffraction pattern of form a of compound (I) (referred to herein as form a) showing degrees 2 θ (2-theta) on the X-axis and relative intensities on the Y-axis.

Figure 2 shows a Differential Scanning Calorimetry (DSC) thermogram for form a of compound (I).

Figure 3 shows the thermogravimetric coupling of fourier transform infrared spectroscopy (TG-FTIR) of form a of compound (I) as a thermal profile.

Figure 4A shows an X-ray powder diffraction pattern of form B of compound (I) comprising 95% to 99% (E) -isomer (referred to herein as form B) and shows the degrees 2 θ (2-theta) on the X-axis and the relative intensities on the Y-axis.

Figure 4B shows an X-ray powder diffraction pattern of form B of compound (I) containing >99% (E) -isomer, with degrees 2 θ (2-theta) shown on the X-axis and relative intensities shown on the Y-axis.

Fig.5A shows a Differential Scanning Calorimetry (DSC) thermogram of form B of compound (I) comprising 95% to 99% (E) -isomer.

Figure 5B shows a Differential Scanning Calorimetry (DSC) thermogram of form B of compound (I) comprising >99% (E) -isomer.

Figure 6A shows the thermogravimetric plot of crystalline form B of compound (I) containing 95 to 99% (E) -isomer combined with fourier transform infrared spectroscopy (TG-FTIR).

Figure 6B shows the thermogravimetric combined fourier transform infrared spectroscopy (TG-FTIR) thermogravimetric curves of form B of compound (I) containing >99% (E) -isomer.

Fig.7 shows an X-ray powder diffraction pattern of form C of compound (I) (referred to herein as form C) showing degrees 2 theta (2-theta) on the X-axis and relative intensities on the Y-axis.

Figure 8 shows a Differential Scanning Calorimetry (DSC) thermogram and thermogravimetric analysis thermodynamic curve for form C, wherein the scan rate is 15 ℃/min.

Figure 9 shows a Differential Scanning Calorimetry (DSC) thermogram and a thermogravimetric analysis of form C with a scan rate of 10 ℃/min.

Figure 10 shows the thermogravimetric combined fourier transform infrared spectroscopy (TG-FTIR) thermogram of form C.

Fig.11 shows a single crystal structure of form C.

Defining:

as used herein, "a" or "an" entity refers to one or more of that entity, e.g., "a compound" refers to one or more of that compound or at least one of that compound, unless otherwise specified. Thus, the terms "a" (or "an"), "one or more (one or more)" and "at least one (at least one)" are used interchangeably herein.

As used herein, the term "about" means about, within, about, or around an area. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. Generally, the term "about" is used herein to modify a numerical value above and below the stated value by a difference of 5%.

As used herein, "compound (I)" means (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pentan-2-enenitrile, (E) isomer of S) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pentan-2-enenitrile, (Z) isomer or a mixture of (E) and (Z) isomers, or a mixture of 2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazine-1-yl ] pentanenitrile (R) and a mixture of (S) enantiomers, the compounds have the following structure:

wherein C is a stereochemical centre.

When compound (I) is represented by (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile, it may contain less than 1% by weight of the corresponding (S) enantiomer as an impurity. Correspondingly, when compound (I) is represented as a mixture of the (R) and (S) enantiomers of 2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile, the amount of the (R) or (S) enantiomer in the mixture is more than 1% by weight. Similarly, when compound (I) is represented as the (E) isomer, it may contain less than 1% by weight of the corresponding (Z) isomer as an impurity. Accordingly, when compound (I) is represented as a mixture of (E) and (Z) isomers of 2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile, the amount of (E) or (Z) isomer in the mixture is greater than 1% by weight.

As used herein, "crystalline form [ X ] of compound (I) comprising [ Y ]% (E) -isomer" means that [ Y ]% of compound (I) in the crystalline form is (E) isomer.

Herein, compound (I) may be referred to as a "drug", "active agent", "therapeutically active agent" or "API".

As used herein, "substantially pure" in relation to geometric isomeric forms refers to compounds, such as compound (I), wherein more than 70% by weight of the compound is present in a given isomeric form. For example, the phrase "form a of compound (I) is a substantially pure (E) isomer of compound (I)" means that at least 70% by weight of form a of compound (I) in form a of compound (I) is in the form of the (E) isomer, and the phrase "form a of compound (I) is a substantially pure (Z) isomer of compound (I)" means that at least 70% by weight of form a of compound (I) in form a of compound (I) is in the (Z) isomer form. In some embodiments, at least 80% by weight of the crystalline form of compound (I) is in form (E), or at least 80% by weight of the crystalline form of compound (I) is in form (Z). In some embodiments, at least 85% by weight of the crystalline form of compound (I) is in the (E) form, or at least 85% by weight of the crystalline form of compound (I) is in the (Z) form. In some embodiments, at least 90% by weight of the crystalline form of compound (I) is in form (E), or at least 90% by weight of the crystalline form of compound (I) is in form (Z). In some embodiments, at least 95% by weight of the crystalline form of compound (I) is in the (E) form, or at least 95% by weight of the crystalline form of compound (I) is in the (Z) form. In some embodiments, at least 97% by weight or at least 98% by weight of the crystalline form of compound (I) is in the form (E), or at least 97% by weight or at least 98% by weight of the crystalline form of compound (I) is in the form (Z). In some embodiments, at least 99% by weight of the crystalline form of compound (I) is in the (E) form, or at least 99% by weight of the crystalline form of compound (I) is in the (Z) form. (E) The relative amounts of (Z) isomer and (Z) isomer in the solid mixture can be determined according to standard methods and techniques known in the art.

As used herein, "pharmaceutically acceptable excipient" refers to a carrier or excipient used in the preparation of a pharmaceutical composition. For example, pharmaceutically acceptable excipients are generally safe and include carriers and excipients generally recognized as being pharmaceutically acceptable for mammals.

As used herein, the terms "polymorph," "crystal Form," and "Form" interchangeably refer to a solid having a particular packing arrangement of molecules in a crystal lattice. The crystalline forms may be identified and distinguished from one another by at least one characterization technique including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential Scanning Calorimetry (DSC), dynamic Vapor Sorption (DVS), and/or thermogravimetric analysis (TGA). Thus, as used herein, the term "crystalline form [ X ] of compound (I)" refers to a unique crystalline form that can be identified and distinguished from other forms by at least one characterization technique, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential Scanning Calorimetry (DSC), dynamic vapor adsorption (DVS), and/or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of the present disclosure are characterized by an X-ray powder diffraction pattern having at least one signal at least one specified 2-theta value (° 2 Θ).

As used herein, a "therapeutically effective amount" of a compound disclosed herein refers to the amount of the compound that will elicit a biological or medical response in a subject. A therapeutically effective amount will depend on The therapeutic purpose and will be determined by one of ordinary skill in The Art (see, e.g., lloyd (1999) The Art, science and Technology of Pharmaceutical Compounding).

As used herein, the term "inhibit" ("inhibit", "inhibition" or "inhibiting") refers to a reduction or suppression of a given condition, symptom or disorder or disease, or to a significant reduction in the baseline activity of a biological activity or process.

As used herein, the term "treating," when used in conjunction with a disorder or condition, includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in an improvement in the disorder or condition. Amelioration or palliation of the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art.

As used herein, "mammal" refers to domestic animals (e.g., dogs, cats and horses) and humans. In some embodiments, the mammal is a human. In some embodiments, the mammal is a canine.

As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

As used herein, the term "TGA" refers to an analytical method of thermogravimetric (also known as thermogravimetric) analysis.

As used herein, the term "TG-FTIR" refers to an analytical method of thermogravimetry coupled with fourier transform infrared spectroscopy.

As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD spectra can be recorded in transmission or reflection geometry under ambient conditions using a diffractometer.

As used herein, the terms "X-ray powder diffraction pattern", "X-ray powder diffraction spectrum" and "XRPD spectrum" refer to experimentally obtained spectra plotting signal position (on the abscissa) versus signal intensity (on the ordinate). For crystalline materials, the X-ray powder diffraction pattern may include at least one signal plotted on the abscissa of the X-ray powder diffraction pattern, each signal being identified by measuring an angular value in degrees 2 θ (° 2 θ), which may be expressed as "signal at \8230; 8230; degree 2 θ", "signal at one or more 2 θ values of \8230;" signal at least 8230; 2 θ values selected from \8230; "signal at least 8230; \8230; 8230; 2 θ values").

As used herein, the term "X-ray powder diffraction pattern having a signal at a value of \8230;. 2 θ" refers to an XRPD pattern containing the X-ray reflection positions measured and observed in an X-ray powder diffraction experiment (° 2 θ).

As used herein, the term "signal" refers to the point in an XRPD spectrum where the counts of measured intensity are at local maxima. One of ordinary skill in the art will recognize that at least one signal in an XRPD spectrum may overlap and may be, for example, not apparent to the naked eye. One of ordinary skill in the art will recognize that several art-recognized methods, such as teved's algorithm, are capable of and suitable for determining whether a signal is present in a map.

As used herein, the terms "signal at \8230: \823030; 2 theta values", "signal at one or more 2 theta values of \8230; \8230and" signal at least 8230selected from \8230; 2 theta values "refer to the positions of X-ray reflections measured and observed in X-ray powder diffraction experiments (° 2 theta). In some embodiments, the angular value has a repeatability in the range of ± 0.2 ° 2 θ, i.e., the angular value can be the angular value +0.2 ° 2 θ, the angular value-0.2 ° 2 θ, or any value between these two endpoints (angular value +0.2 ° 2 θ and angular value-0.2 ° 2 θ). It is well known to those of ordinary skill in the art that there may be variability in the measurement of the X-ray powder diffraction signal values. Thus, one of ordinary skill in the art will appreciate that there can be variability in signal values for the same signal in different samples up to ± 0.2 ° 2 θ. In addition, it is well known to those of ordinary skill in the art that there can be variability in the measurement of relative signal intensity in X-ray powder diffraction experiments. Illustratively, non-limiting factors that can affect relative signal intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

As used herein, an X-ray powder diffraction pattern "is substantially similar to a [ particular ] pattern" when the signals ± 0.2 ° 2 Θ of at least 90%, such as at least 95%, at least 98%, or at least 99% of the two diffraction patterns are the same. In determining "substantial similarity," one of ordinary skill in the art will appreciate that there will be variations in intensity and/or signal position in the XRPD diffractogram, even for the same crystalline form. Thus, those of ordinary skill in the art will appreciate that the signal maximum in an XRPD diffractogram (degrees 2 θ (° 2 θ) as referred to herein) generally means ± 0.2 ° 2 θ of the reported value of the value report, which is the art-recognized variation discussed above.

As noted above, novel crystalline forms of compound (I) are described herein. These novel crystalline forms may be inhibitors of BTK. BTK inhibitors are useful for treating diseases mediated by BTK, such as pemphigus vulgaris, pemphigus foliaceus, and immune thrombocytopenia.

The implementation scheme is as follows:

non-limiting embodiments of the present disclosure include:

1. a crystalline form A of Compound (I):

wherein C is a stereochemical centre.

2. Form a according to embodiment 1, characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2.

3. Form a according to embodiment 1 or 2, characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern of figure 1.

4. Form a according to any one of embodiments 1-3, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 146 ℃ to about 147 ℃.

5. Form a according to any one of embodiments 1-4, characterized by a DSC thermogram showing an onset of melting at about 140.6 ℃ to about 141.2 ℃.

6. Form a according to any of embodiments 1-5, characterized in that the mass loss between 25 ℃ and 200 ℃ is less than 1.0wt.% by thermogravimetric analysis.

7. Form a according to any one of embodiments 1 to 6, characterized by a water content of less than 1% when stored at 95% Relative Humidity (RH).

8. Form a according to any one of embodiments 1-7, wherein at least 95% of compound (I) is the (E) isomer.

9. A crystalline form a of compound (I) prepared by a process comprising:

adding isopropyl acetate to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution;

stirring the solution to form a precipitate; and

isolate form a by filtration.

10. A crystalline form B of Compound (I):

wherein C is a stereochemical center.

11. Form B according to embodiment 10, characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.0 ± 0.2, and 22.9 ± 0.2.

12. Form B according to embodiment 10 or 11, wherein at least >99% of compound (I) is the (E) -isomer.

13. Form B according to embodiment 10 or 11, wherein 95 to 99% of compound (I) is the (E) -isomer.

14. Form B according to any one of embodiments 10-12, characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern of figure 4B.

15. Form B according to any one of embodiments 10, 11, or 13, characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern of figure 4A.

16. Form B according to any of embodiments 10-12 or 14, characterized by a DSC thermogram with an endotherm (melting temperature) at about 144 ℃ to about 146 ℃.

17. Form B according to any of embodiments 10-12, 14 or 16, characterized by a DSC thermogram showing an onset of melting at about 139.3 ℃.

18. The crystalline form B according to any one of embodiments 10, 11, 13, or 15, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 141 ℃ to about 142 ℃.

19. Form B according to any one of embodiments 10, 11, 13, 15 or 18, characterized by a DSC thermogram showing an onset of melting at about 131.8 ℃ to about 132.4 ℃.

20. Form B according to any one of embodiments 10-19, characterized by a water content of less than 1.3% when stored at 95% Relative Humidity (RH).

21. A crystalline form B of compound (I) prepared by a process comprising:

adding ethyl acetate to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution;

inoculating the solution with sodium chloride and stirring the solution to obtain a suspension;

isolating form B by filtering the suspension.

22. A crystalline form B of compound (I) prepared by a process comprising:

adding ethanol to form C of (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution or slurry;

seeding the solution or the slurry with seed crystals of form B of compound (I); and

isolating compound (I) in crystalline form B by filtration.

23. A crystalline form C of Compound (I):

wherein C is a stereochemical centre.

24. Form C according to embodiment 23, characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2.

25. Form C according to embodiment 23 or 24, characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern of figure 7.

26. Form C according to any one of embodiments 23-25, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 118.5 ℃ to about 119 ℃, wherein the DSC scan rate is 15 ℃/min.

27. Form C according to any one of embodiments 23-26, characterized by a DSC thermogram showing an onset of melting at about 115.6 ℃ to about 116 ℃, wherein the DSC scan rate is 15 ℃/min.

28. Form C according to any one of embodiments 23-27, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 120.5 ℃ to about 121 ℃, wherein the DSC scan rate is 10 ℃/min.

29. Form C according to any one of embodiments 23-28, characterized by a DSC thermogram showing an onset of melting at about 118 ℃ to about 118.5 ℃, wherein the DSC scan rate is 10 ℃/min.

30. The crystalline form C according to any one of embodiments 23-29, wherein at least 95% of compound (I) is the (E) isomer.

31. The crystalline form C according to any one of embodiments 23-30, characterized by a P-1 space group.

32. Form C according to any one of embodiments 23-31, characterized by the following unit cell dimensions at 200 (2) K:

α＝93.654°

β＝104.400°

γ＝105.476°。

33. a crystalline form C of compound (I) prepared by a process comprising:

adding acetonitrile to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution;

inoculating the solution with form B of compound (I) to form a mixture and stirring the mixture to obtain a slurry; and

isolating form C by filtering the slurry.

34. A pharmaceutical composition, comprising:

at least one crystalline form of compound (I) selected from the crystalline forms according to any one of embodiments 1-33; and

at least one pharmaceutically acceptable excipient.

35. The pharmaceutical composition of embodiment 34, wherein the pharmaceutical composition is in the form of a solid oral composition.

36. The pharmaceutical composition of embodiment 34 or 35, wherein the pharmaceutical composition is in the form of a tablet or capsule.

37. A method of inhibiting Bruton's Tyrosine Kinase (BTK) in a mammal, comprising administering to a mammal in need of said BTK inhibition a therapeutically effective amount of at least one crystalline form selected from the crystalline forms according to any one of embodiments 1-33.

38. A method of treating a disease mediated by Bruton's Tyrosine Kinase (BTK) in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms according to any one of embodiments 1-33.

39. A method of treating pemphigus vulgaris or pemphigus foliaceus in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms according to any one of embodiments 1-33.

40. A method of treating immune thrombocytopenia in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms according to any one of embodiments 1-33.

41. The method according to any one of embodiments 37-40, wherein the mammal is a human.

Form a of compound (I):

in some embodiments, the present disclosure provides crystalline form a of compound (I):

wherein C is a stereochemical centre.

Figure 1 shows an X-ray powder diffraction pattern of form a of compound (I). In fig.1, the XRPD pattern corresponds to form a with a small amount of form B, which is further described below.

Figure 2 shows the DSC thermogram of form a of compound (I). In some embodiments, form a of compound (I) is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 146 ℃ to about 147 ℃. In some embodiments, form a of compound (I) is characterized by a DSC thermogram showing an onset of melting/decomposition at about 140.6 ℃ to about 141.2 ℃. In some embodiments, form a of compound (I) is characterized by a DSC thermogram showing an onset of melting at about 140.6 ℃ to about 141.2 ℃. In some embodiments, the associated enthalpy is about 52J/g (Δ H = 52J/g).

In some embodiments, form a of compound (I) is characterized by a DSC thermogram substantially similar to the one set forth in figure 2.

In some embodiments, form a of compound (I) is characterized by a thermogravimetric-coupled fourier transform infrared spectroscopy (TG-FTIR) thermogram substantially similar to the one in figure 3. In some embodiments, form a of compound (I) is characterized by a mass loss between 25 ℃ and 200 ℃ of less than 1.0wt.% by thermogravimetric analysis. In some embodiments, the mass loss corresponds to a loss of isopropyl acetate released near the melting temperature. In some embodiments, decomposition is observed at higher temperatures (starting at about 220 ℃ to about 230 ℃), e.g., substantially as shown in figure 3.

In some embodiments, form a of compound (I) has a water content of less than 1% when stored at 85% Relative Humidity (RH).

In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis of an incident beam irradiated with Cu ka radiation having signals substantially similar to those described in table 1.

Table 1.

2-theta (degree)
	5.64
10.19
	10.49
12.50
	12.71
16.49
	17.01
17.72
	18.67
19.16
	19.51
20.68
	21.15
22.21
	23.41
24.38
	25.08
25.59
	20.29
26.92
	27.50

In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 5.6 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 12.7 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.5 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 17.0 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 17.7 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 19.2 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 20.7 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.2 ± 0.2 ° 2 Θ. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 24.4 ± 0.2 ° 2 Θ.

In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 2 Θ values of 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least nine 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least eight 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least seven 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least six 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least five 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least four 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least two 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at least one 2 Θ value selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2.

In some embodiments, form a of compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in fig. 1.

In some embodiments, the present disclosure provides a method of preparing form a of compound (I), the method comprising: isopropyl acetate was added to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution. In some embodiments, the method further comprises agitating the solution to form a precipitate. In some embodiments, the method further comprises isolating form a by filtration.

In some embodiments, the present disclosure provides crystalline form a of compound (I) prepared by a process comprising: isopropyl acetate was added to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution. In some embodiments, the method further comprises agitating the solution to form a precipitate. In some embodiments, the method further comprises isolating form a by filtration.

Crystal form B of compound (I)

In some embodiments, the present disclosure provides crystalline form B of compound (I):

wherein C is a stereochemical centre.

Fig.4A shows an X-ray powder diffraction pattern of form B of compound (I) comprising 95 to 99% (E) -isomer. In fig.4A, the XRPD pattern corresponds to form B obtained without NaCl seeds by: the use of crystalline forms a and B seeds added in a stirred solution of amorphous compound (I) in ethyl acetate followed by stirring overnight resulted in the production of crystals and form B.

Figure 4B shows an X-ray powder diffraction pattern of form B of compound (I) containing >99% (E) -isomer. In fig.4B, the XRPD pattern corresponds to form B obtained without NaCl seeding by: the use of crystalline form B seeds added in a stirred slurry of form C of compound (I) in ethanol followed by stirring overnight resulted in crystallization and the production of crystalline form B comprising more than 99% (E) -isomer.

Over time, form a may transform to form B. Thus, form B is thermodynamically more stable than form a at room temperature.

Over time, form C may convert to form B. Thus, form B is thermodynamically more stable than form C at room temperature.

Fig.5A shows a DSC thermogram of form B of compound (I) comprising 95 to 99% (E) -isomer.

In some embodiments, form B of compound (I) is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 141 ℃ to about 142 ℃. In some embodiments, form B of compound (I) is characterized by a DSC thermogram showing an onset of melting/decomposition at about 131.8 ℃ to about 132.4 ℃. In some embodiments, form B of compound (I) is characterized by a DSC thermogram showing an onset of melting at about 131.8 ℃ to about 132.4 ℃. In some embodiments, the associated enthalpy is about 54.9J/g (Δ H = 54.9J/g).

In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 141 ℃ to about 142 ℃. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by a DSC thermogram showing an onset of melting/decomposition at about 131.8 ℃ to about 132.4 ℃. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by a DSC thermogram showing an onset of melting at about 131.8 ℃ to about 132.4 ℃. In some embodiments, the associated enthalpy is about 54.9J/g (Δ H = 54.9J/g).

In some embodiments, form B of compound (I) is characterized by a DSC thermogram substantially similar to the one in figure 5A. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by a DSC thermogram substantially similar to the one set forth in fig. 5A.

Figure 5B shows a DSC thermogram for form B containing >99% (E) -isomer.

In some embodiments, the crystalline form of compound (I) is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 144 ℃ to about 146 ℃. In some embodiments, form B of compound (I) is characterized by a DSC thermogram showing an onset of melting at about 139.3 ℃. In some embodiments, the associated enthalpy is about 65.5J/g (Δ H = 65.5J/g).

In some embodiments, the crystalline form of compound (I) comprising >99% (E) -isomer is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 144 ℃ to about 146 ℃. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by a DSC thermogram showing an onset of melting at about 139.3 ℃. In some embodiments, the associated enthalpy is about 65.5J/g (Δ H = 65.5J/g).

In some embodiments, form B of compound (I) is characterized by a DSC thermogram substantially similar to the one in figure 5B. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by a DSC thermogram substantially similar to the one in fig. 5B.

In some embodiments, crystalline form B of compound (I) is characterized by a thermogravimetric-fourier transform infrared spectroscopy (TG-FTIR) thermogram substantially similar to the one set forth in fig. 6A. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by a thermogravimetric-coupled fourier transform infrared spectroscopy (TG-FTIR) thermogram substantially similar to the one in fig. 6A.

In some embodiments, form B of compound (I) is characterized by a mass loss between 25 ℃ and 162 ℃ of less than 0.8wt.% by thermogravimetric analysis. In some embodiments, in addition to the mass loss described above, there is a further mass loss of less than 0.8wt.% between 162 ℃ and 250 ℃ by thermogravimetric analysis. In some embodiments, the further mass loss corresponds to the removal of ethyl acetate. In some embodiments, decomposition is observed at higher temperatures (starting at about 250 ℃ to about 253 ℃), e.g., substantially as shown in fig. 6A.

In some embodiments, the crystalline form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by a mass loss between 25 ℃ and 162 ℃ of less than 0.8wt.% by thermogravimetric analysis. In some embodiments, in addition to the mass loss described above, there is a further mass loss of less than 0.8wt.% between 162 ℃ and 250 ℃ by thermogravimetric analysis. In some embodiments, the further mass loss corresponds to the removal of ethyl acetate. In some embodiments, decomposition is observed at higher temperatures (starting at about 250 ℃ to about 253 ℃), e.g., substantially as shown in fig. 6A.

In some embodiments, form B of compound (I) is characterized by a thermogravimetric combined fourier transform infrared spectroscopy (TG-FTIR) thermogram substantially similar to the one in fig. 6B. In some embodiments, crystalline form B of compound (I) comprising >99% (E) -isomer is characterized by a thermogravimetric-coupled fourier transform infrared spectroscopy (TG-FTIR) thermogram substantially similar to the one in fig. 6B.

In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by a mass loss between 25 ℃ and 162 ℃ of less than 0.7wt.% by thermogravimetric analysis. In some embodiments, in addition to the mass loss described above, there is a further mass loss of less than 0.7wt.% between 162 ℃ and 250 ℃ by thermogravimetric analysis. In some embodiments, the further mass loss corresponds to the removal of ethanol. In some embodiments, decomposition is observed at higher temperatures (starting at about 250 ℃ to about 253 ℃), e.g., substantially as shown in figure 6A.

In some embodiments, crystalline form B of compound (I) comprising >99% (E) -isomer is characterized by a mass loss between 25 ℃ and 162 ℃ of less than 0.5wt.% by thermogravimetric analysis. In some embodiments, in addition to the mass loss described above, there is a further mass loss of less than 0.5wt.% between 162 ℃ and 250 ℃ by thermogravimetric analysis. In some embodiments, the further mass loss corresponds to the removal of ethanol. In some embodiments, decomposition is observed at higher temperatures (starting at about 250 ℃ to about 253 ℃), e.g., substantially as shown in fig. 6B.

In some embodiments, form B of compound (I) is characterized by a water content of less than 1.3% when stored at 95% Relative Humidity (RH). In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by a water content of less than 1.3% when stored at 95% Relative Humidity (RH).

In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis of an incident beam irradiated with Cu ka radiation having signals substantially similar to those described in table 2A. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis of an incident beam irradiated with Cu ka radiation having signals substantially similar to those described in table 2A.

Table 2A.

In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 10.8 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 15.3 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.3 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 17.9 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.9 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 23.1 ± 0.2 ° 2 Θ.

In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 10.8 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 15.3 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 16.3 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 17.9 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 22.9 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 23.1 ± 0.2 ° 2 Θ.

In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2 Θ values of 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2 and 23.1 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least seven 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least six 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least five 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least four 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least two 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at least one 2 Θ value selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2.

In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 2 Θ values of 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at least seven 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least six 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at least five 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least four 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least two 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at least one 2 Θ value selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2.

In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern of fig. 4A. In some embodiments, form B of compound (I) comprising 95% to 99% (E) -isomer is characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in fig. 4A.

In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis of an incident beam irradiated with Cu ka radiation having signals substantially similar to those described in table 2B. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis of an incident beam of radiation with Cu ka having signals substantially similar to those described in table 2B.

Table 2B.

2-theta (degree)
	4.22
5.13
	10.76
11.97
	13.24
13.90
	14.54
15.31
	16.34
16.67
	17.03
17.47
	17.89
18.36
	18.69
19.17
	19.50
20.44
	20.77
21.15
	21.67
22.05
	22.35
22.93
	23.42
23.86
	24.12
24.40
	24.79
25.53
	26.03
26.47
	28.26
28.86
	30.45
30.87
	31.95
33.48
	35.33
36.75

In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern at 4.2 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 5.1 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 10.8 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 15.3 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.3 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 17.9 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 19.2 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 21.2 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.0 ± 0.2 ° 2 Θ.

In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern at 4.2 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 5.1 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 10.8 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 15.3 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 16.3 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 17.9 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 19.2 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 21.2 ± 0.2 ° 2 Θ. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 22.0 ± 0.2 ° 2 Θ.

In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 2 Θ values of 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at least ten 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least nine 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least eight 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least seven 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least six 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least five 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least four 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least two 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at least one 2 Θ value selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2.

In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at 2 Θ values of 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at least ten 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least nine 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least eight 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least seven 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least six 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least five 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least four 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having signals at least two 2 Θ values selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern having a signal at least one 2 Θ value selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2.

In some embodiments, form B of compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in fig. 4B. In some embodiments, form B of compound (I) comprising >99% (E) -isomer is characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in fig. 4B.

In some embodiments, the present disclosure provides crystalline form B of compound (I) prepared by a process comprising: ethyl acetate was added to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution. In some embodiments, the method further comprises inoculating the solution with sodium chloride and stirring to obtain a suspension. In some embodiments, the method further comprises isolating form B by filtering the suspension.

In some embodiments, the present disclosure provides a method of preparing crystalline form B of compound (I), the method comprising: amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile was dissolved in ethyl acetate to form a solution. In some embodiments, the method further comprises seeding the solution with a mixture of form a of compound (I) and forms a and B of compound (I) to obtain a slurry. In some embodiments, the process further comprises adding heptane to the slurry and filtering the slurry to obtain form B of compound (I).

In some embodiments, the present disclosure provides crystalline form B of compound (I) prepared by a process comprising: amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile is dissolved in ethyl acetate to form a solution. In some embodiments, the method further comprises seeding the solution with a mixture of form a of compound (I) and forms a and B of compound (I) to obtain a slurry. In some embodiments, the method further comprises adding heptane to the slurry and filtering the slurry to obtain form B of compound (I).

In some embodiments, the present disclosure provides crystalline form B of compound (I) comprising 95% to 99% (E) -isomer prepared by a process comprising: ethyl acetate was added to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution. In some embodiments, the method further comprises inoculating the solution with sodium chloride and stirring to obtain a suspension. In some embodiments, the method further comprises isolating form B comprising 95% to 99% (E) -isomer by filtering the suspension.

In some embodiments, the present disclosure provides a method of preparing form B of compound (I) comprising 95% to 99% (E) -isomer, the method comprising: amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile was dissolved in ethyl acetate to form a solution. In some embodiments, the method further comprises seeding the solution with a mixture of form a of compound (I) and forms a and B of compound (I) to obtain a slurry. In some embodiments, the process further comprises adding heptane to the slurry and filtering the slurry to obtain form B of compound (I) comprising 95% to 99% (E) -isomer.

In some embodiments, the present disclosure provides crystalline form B of compound (I) comprising 95% to 99% (E) -isomer prepared by a process comprising: amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile is dissolved in ethyl acetate to form a solution. In some embodiments, the method further comprises seeding the solution with a mixture of form a of compound (I) and forms a and B of compound (I) to obtain a slurry. In some embodiments, the process further comprises adding heptane to the slurry and filtering the slurry to obtain form B of compound (I) comprising 95% to 99% (E) -isomer.

In some embodiments, the present disclosure provides a method of preparing crystalline form B of compound (I), the method comprising: form C of compound (I) is dissolved in ethanol to form a solution or slurry. In some embodiments, the method further comprises seeding the solution or slurry with form B of compound (I). In some embodiments, the method further obtains a precipitate by filtration. In some embodiments, the method further comprises drying the precipitate under vacuum to obtain form B of compound (I). In some embodiments, drying the precipitate under vacuum comprises applying heat.

In some embodiments, form C dissolves at about 15 ℃. In some embodiments, the solution or slurry seeded with form B is stirred at room temperature for a period of time. In some embodiments, the period of time is about 48 hours.

In some embodiments, the present disclosure provides a method of preparing form B of compound (I) comprising >99% (E) -isomer, the method comprising: form C of compound (I) is dissolved in ethanol to form a solution or slurry. In some embodiments, the method further comprises seeding the solution or slurry with form B of compound (I). In some embodiments, the method further obtains a precipitate by filtration. In some embodiments, the method further comprises drying the precipitate under vacuum to obtain form B of compound (I) comprising >99% (E) -isomer. In some embodiments, drying the precipitate under vacuum comprises applying heat.

Crystalline form C of Compound (I)

In some embodiments, the present disclosure provides crystalline form C of compound (I):

wherein C is a stereochemical centre.

Form C is an acetonitrile solvate of compound (I).

Figure 7 shows an X-ray powder diffraction pattern of form C of compound (I).

Figure 8 shows the DSC thermogram for form C of compound (I). In some embodiments, form C of compound (I) is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 118.5 ℃ to about 119 ℃. In some embodiments, form C of compound (I) is characterized by a DSC thermogram showing an onset of melting/decomposition at about 115.6 ℃ to about 116.0 ℃. In some embodiments, form C of compound (I) is characterized by a DSC thermogram showing an onset of melting at about 115.6 ℃ to about 116.0 ℃.

Figure 8 also shows the TGA thermogram of form C of compound (I). In some embodiments, form C is characterized by a mass loss of less than 5% between 25 ℃ and 150 ℃.

Using a sample prepared with an autosampler and at 40mL/min N ₂ The DSC thermogram in fig.8 was obtained with a TA instruments Q100 or Q2000 differential scanning calorimeter of a refrigerated cooling system under purge. DSC thermograms of the screened samples were obtained at 15 deg.C/min in a coiled Al pan. In Pt or Al disks at 40mL/min N ₂ TGA thermograms were obtained with a TA instruments Q50 thermogravimetric analyzer under purge. Unless otherwise indicated, the TGA thermograms of the screened samples were obtained at 15 ℃/min.

Figure 9 shows different DSC thermograms for form C of compound (I). The condition of the DSC is the same as that of FIG.8 except that the temperature scan rate is 10 deg.C/min. In some embodiments, form C of compound (I) is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 120.5 ℃ to about 121 ℃. In some embodiments, form C of compound (I) is characterized by a DSC thermogram showing an onset of melting/decomposition at about 118.0 ℃ to about 118.5 ℃.

Figure 9 also shows the TGA thermogram of form C of compound (I). The TGA profile is the same as in FIG.8, except the temperature sweep rate is 10 deg.C/min. In some embodiments, form C is characterized by a mass loss between 25 ℃ and 145 ℃ of less than 5wt.%. In some embodiments, the mass loss is due to removal of acetonitrile.

In some embodiments, form C of compound (I) undergoes decomposition at higher temperatures (above 250 ℃), for example, as shown by the TG-FTIR thermogram of form C in fig. 10. Figure 10 also shows that there is a mass loss of less than 5.5% between 100 ℃ and 200 ℃. In some embodiments, the mass loss is due to loss of acetonitrile.

In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis of an incident beam irradiated with Cu ka radiation having signals substantially similar to those described in table 3.

Table 3.

In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 9.8 ± 0.2 ° 2 Θ. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 10.2 ± 0.2 ° 2 Θ. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 15.6 ± 0.2 ° 2 Θ. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.6 ± 0.2 ° 2 Θ. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.6 ± 0.2 ° 2 Θ. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.9 ± 0.2 ° 2 Θ. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 19.6 ± 0.2 ° 2 Θ. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 21.6 ± 0.2 ° 2 Θ.

In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2 Θ values of 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at least seven 2 Θ values selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least six 2 Θ values selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least five 2 Θ values selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least four 2 Θ values selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having signals at least two 2 Θ values selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at least one 2 Θ value selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2.

In some embodiments, form C of compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in fig. 7.

In some embodiments, form C of compound (I) is characterized by a single crystal structure substantially similar to the single crystal structure in fig. 11.

In some embodiments, form C of Compound (I) is characterized by the P-1 space group.

In some embodiments, form C of compound (I) is characterized by a P-1 space group and the following unit cell sizes:

α＝93.65°

β＝104.40°

γ＝105.48°。

α＝93.654°

β＝104.400°

γ＝105.476°。

in some embodiments, form C of compound (I) is characterized by the P-1 space group and the following unit cell dimensions:

α＝93.6543°

β＝104.4003°

γ＝105.4764°。

α＝93.6543°

β＝104.4003°

γ＝105.4764°。

α＝93.6543°

β＝104.4003°

γ＝105.4764°。

in some embodiments, form C of compound (I) is characterized by a P-1 space group and the following unit cell dimensions at 200 (2) K:

α＝93.65°

β＝104.40°

γ＝105.48°。

α＝93.654°

β＝104.400°

γ＝105.476°。

α＝93.6543°

β＝104.4003°

γ＝105.4764°。

in some embodiments, form C of compound (I) is characterized by the P-1 space group and the following unit cell dimensions at 200 (2) K:

α＝93.6543°

β＝104.4003°

γ＝105.4764°。

α＝93.6543°

β＝104.4003°

γ＝105.4764°。

in some embodiments, the present disclosure provides a method of preparing crystalline form C of compound (I), the method comprising: acetonitrile was added to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution. In some embodiments, the method further comprises seeding the solution with form B of compound (I) to form a mixture and stirring the mixture to obtain a slurry. In some embodiments, the method further comprises isolating form C by filtering the slurry.

In some embodiments, the present disclosure provides crystalline form C of compound (I) prepared by a process comprising: acetonitrile was added to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution. In some embodiments, the method further comprises seeding the solution with form B of compound (I) to form a mixture and stirring the mixture to obtain a slurry. In some embodiments, the method further comprises isolating form C by filtering the slurry.

In some embodiments, the present disclosure provides a method of preparing crystalline form C of compound (I), the method comprising: acetonitrile was added to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution. In some embodiments, the method further comprises inoculating the solution with form C of compound (I) and stirring to obtain a precipitate. In some embodiments, the method further comprises isolating form C by filtering the precipitate. In some embodiments, the method further comprises drying the precipitate under vacuum to obtain form C of compound (I).

In some embodiments, the present disclosure provides crystalline form C of compound (I) prepared by a process comprising: acetonitrile was added to amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile to form a solution. In some embodiments, the method further comprises inoculating the solution with form C of compound (I) and stirring to obtain a precipitate. In some embodiments, the method further comprises isolating form C by filtering the precipitate. In some embodiments, the method further comprises drying the precipitate under vacuum to obtain form C of compound (I).

In some embodiments, the present disclosure provides a method of preparing crystalline form C of compound (I), the method comprising: stirring a mixture of amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile and a mixture of compound (I) crystalline forms A and B in an acetonitrile/tert-butyl methyl ether mixture. In some embodiments, the process further comprises seeding the mixture with form a of compound (I), and optionally further adding an additional amount of acetonitrile/tert-butyl methyl ether mixture to obtain a suspension. In some embodiments, the suspension is a thick suspension. In some embodiments, the method further comprises isolating form C by filtering the suspension.

In some embodiments, the present disclosure provides crystalline form C of compound (I) prepared by a process comprising: stirring a mixture of amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile and a mixture of compound (I) crystalline forms A and B in an acetonitrile/tert-butyl methyl ether mixture. In some embodiments, the process further comprises seeding the mixture with form a of compound (I), and optionally further adding an additional amount of acetonitrile/tert-butyl methyl ether mixture to obtain a suspension. In some embodiments, the suspension is a thick suspension. In some embodiments, the method further comprises isolating form C by filtering the suspension.

Indication card

The crystalline forms of compound (I) described herein may be used to treat a disorder mediated by BTK activity in a mammal. In some embodiments, the crystalline forms of compound (I) described herein may be used for the treatment of a human or non-human.

The crystalline forms of compound (I) described herein may be used for the treatment of various conditions or diseases, <xnotran> , , , , , , , , , , , , - , TEN , , , , (leucoclastic vasculitis), , , , , , (sweet syndrome), , , , , , , , , , , , (Wegener's granulomatosis), , , , , , , , B , , , , B , / (Waldenstrom macroglobulinemia), , , , B , B , , () B , , B , , / . </xnotran>

Pemphigus is a rare B-cell mediated autoimmune disease that causes debilitating intraepithelial blisters and erosion on the skin and/or mucosa. Pemphigus has a mortality rate of 10% (usually due to infection and treatment side effects caused by damaged tissues) and approximately 0.1 to 0.5 of 10 million people are affected each year (sculely et al, 2002, sculely et al, 1999. The characteristic intraepidermal blisters observed in pemphigus patients are caused by: igG autoantibodies bind to certain keratinocyte desmoglein proteins desmoglein 1 and 3 (Dsg 1 and Dsg 3), resulting in loss of cell adhesion (Amagai M et al, 2012, diaz LA et al, 2000. B cells play a key role in the production of these autoantibodies and in cellular tolerance mechanisms.

Immune thrombocytopenia (commonly referred to as ITP) is characterized by autoantibody-mediated platelet destruction and impaired thrombopoiesis, leading to thrombocytopenia and a bleeding tendency associated with morbidity and mortality. There is preliminary evidence to support the role of BTK inhibition in patients with autoimmune cytopenia (Rogers 2016, montillo 2017), where the continuous onset of severe autoimmune hemolytic anemia and ITP ceases after an initial treatment with ibrutinib (BTK/EGFR/ITK inhibitor) in patients with Chronic Lymphoid Leukemia (CLL).

Pharmaceutical composition

The crystalline forms described herein are useful as Active Pharmaceutical Ingredients (APIs), as well as materials for preparing pharmaceutical compositions incorporating one or more pharmaceutically acceptable excipients, and are suitable for administration to a human subject. In some embodiments, the pharmaceutical composition will be a pharmaceutical product, e.g., a solid oral dosage form, such as a tablet and/or capsule.

In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one crystalline form of compound (I). In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one crystalline form of compound (I) and at least one additional pharmaceutically acceptable excipient. Each excipient must be "pharmaceutically acceptable" in the sense of being compatible with the subject composition and not deleterious to the patient of its components. Unless any conventional pharmaceutically acceptable excipient is incompatible with compound (I), e.g., produces any undesirable biological effect or otherwise interacts in a deleterious manner with one or more of any of the other components of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of the present disclosure.

Some non-limiting examples of materials that can serve as pharmaceutically acceptable excipients include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) Other non-toxic compatible substances for use in pharmaceutical formulations.

The following documents, the contents of each of which are incorporated herein by reference, also disclose other non-limiting examples of pharmaceutically acceptable excipients and known techniques for making and using them: remington The Science and Practice of Pharmacy, 21 st edition, 2005, editions D.B. Troy, lippincott Williams & Wilkins, philadelphia, and Encyclopedia of Pharmaceutical Technology, editions J.Swarbrick and J.C.Boylan,1988-1999, marcel Dekker, N.Y..

The pharmaceutical compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions of the present disclosure are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the pharmaceutical compositions of the present disclosure may be an aqueous or oleaginous suspension. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

Any bland fixed oil may be employed for this purpose, including synthetic mono-or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils (such as olive oil or castor oil), especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose, or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (e.g., tween, spans) and other emulsifying agents or bioavailability enhancers can also be used for formulation purposes, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms.

The pharmaceutical compositions disclosed herein may also be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions or solutions. When aqueous suspensions are required for oral use, the active ingredient is usually combined with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added, if desired.

Alternatively, the pharmaceutical compositions disclosed herein may be administered in the form of suppositories for rectal administration. Suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the disclosure may also be administered topically, especially when the therapeutic target comprises a region or organ that is readily accessible for topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestinal tract may be achieved by rectal suppository formulations or suitable enema formulations. Topical transdermal patches may also be used.

For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in at least one excipient. Excipients for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions disclosed herein may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in at least one pharmaceutically acceptable excipient. Suitable excipients include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents, and may be prepared as solutions in saline.

Administration of drugs

In general, a therapeutically effective amount of a crystalline form of compound (I) will be administered by any acceptable mode of administration for agents that provide similar utility. An effective dose for any particular mammal (e.g., any particular human) will depend on a variety of factors including: the disorder being treated and the severity of the disorder; the specific pharmaceutical composition employed; the age, weight, general health, sex, and diet of the mammal; time of administration, route of administration, duration of treatment, and the like, as is well known in the medical arts. In some embodiments, a therapeutically effective amount of at least one crystalline form of compound (I) is administered to a mammal in need thereof. A therapeutically effective amount of the crystalline forms disclosed herein may range from 0.01 to 500mg/kg patient body weight per day, which may be administered in single or multiple doses. Suitable dosage levels may be from 0.01 to 250mg/kg per day, from 0.05 to 100mg/kg per day or from 0.1 to 50mg/kg per day. Within this range, in some embodiments, the dose may be 0.05 to 0.5, 0.5 to 5, or 5 to 50mg/kg per day. For oral administration, in some embodiments, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, e.g., 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.

Typically, the crystalline forms of the present disclosure are administered as pharmaceutical compositions by any of the following routes: orally taking; systemic (e.g., transdermal, intranasal, or by suppository); locally; or parenterally (e.g., intramuscularly, intravenously, or subcutaneously). Illustratively, the compositions may take the form of tablets, capsules, semi-solids, powders, sustained release formulations, enteric-coated or delayed release formulations, solutions, suspensions, elixirs, aerosols or any other suitable composition.

All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

Claims or descriptions that include "or" and/or "between at least one member of a group are deemed to be satisfactory if one, more than one, or all of the group members are present in, used in, or otherwise associated with a given product or method, unless the context clearly indicates otherwise or otherwise. The present disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise associated with a given product or method. The present disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise associated with a given product or process.

Furthermore, the disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim may be modified to include at least one limitation found in any other claim that is dependent on the same base claim. Where elements are presented as a list, for example in the form of a markush group, each subgroup of the elements is also disclosed, and one or more of any elements may be removed from the group. It should be understood that, in general, where the present disclosure or aspects of the disclosure are referred to as including particular elements and/or features, embodiments disclosed herein or aspects of the disclosure consist or consist essentially of such elements and/or features. For the sake of simplicity, these embodiments are not explicitly set forth in these words herein. Where ranges are given, the endpoints are inclusive. Furthermore, unless otherwise indicated or clearly understood by the context and understanding of one of ordinary skill in the art, values that are expressed as ranges in different embodiments of the disclosure can assume any specific value or sub-range within the range, to the tenth of the unit of the lower limit of the range (unless the context clearly indicates otherwise).

Those of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims.

Examples

The following examples are intended to be illustrative, and are not intended to limit the scope of the present disclosure in any way.

Analytical method 1: powder X-ray diffraction

Powder X-ray diffraction can be performed with a Stoe Stadi P diffractometer equipped with a Mythen1K detector operating with Cu-K.alpha.1 radiation. The measurements carried out with the instrument can be carried out in transmission at a tube voltage of 40kV and a tube current of 40 mA. A curved Ge monochromator can be used for testing with Cu-K α 1 radiation. The following parameters may be set: a 0.02 ° 2 θ step size, a 12s step time, a 1.5-50.5 ° 2 θ scan range, and a 1 ° 2 θ detector step (detector pattern in step scan). For typical sample preparation, approximately 10mg of sample was placed between two foils of acetic acid and mounted into a Stoe transmission sample holder. The sample was rotated during the measurement. All sample preparation and measurements can be done in an ambient air atmosphere.

Analysis method 2: powder X-ray diffraction (PXRD) PANALYTICAL

PXRD diffractogram can be obtained using Ni-filtered Cu Ka (45 kV/40 mA) radiation and 0.03 DEG 2q step size and X' accelerator ^TM Obtained on a PANalytical X' Pert Pro diffractometer from an RTMS (real time multi-band) detector. The configuration of the incident beam side may be: variable divergence slit (10 mm irradiation length), 0.04rad soller slit, fixedAn anti-scattering slit (0.50 degrees) and a 10mm light-shading frame. The configuration on the diffracted beam side may be: variable anti-scatter slits (10 mm observation length) and 0.04rad soller slits. The samples were mounted flat on zero background Si wafers.

Analysis method 3: differential Scanning Calorimetry (DSC)

Can be prepared with an autosampler and at 40mL/min N ₂ DSC was performed by a TA instruments Q100 or Q2000 differential scanning calorimeter of a refrigerated cooling system under purge. The DSC thermogram of the screened sample can be obtained at 15 ℃/min in a coiled Al pan.

Analysis method 4: thermogravimetric analysis (TGA)

Can be in Pt or Al disk at 40mL/min N ₂ TGA thermograms were obtained with a TA instruments Q50 thermogravimetric analyzer under purge. The TGA thermogram of the screened sample can be obtained at 15 deg.C/min.

Analysis method 5: thermogravimetric analysis coupled with IR outgassing detection (TGA-IR)

TGA-IR can be performed with a TA instruments Q5000 thermogravimetric analyzer (equipped with an external TGA-IR module with gas flow cell and DTGS detector) interfaced with a Nicolet 6700FT-IR spectrometer (Thermo Electron). N at 25mL/min in Pt or Al disks ₂ TGA was performed at a flow rate and a heating rate of 15 deg.C/min. Can be 4cm at each time point ^-1 The IR spectra were collected at resolution and 32 scans.

Analysis method 6: fourier transform Infrared Spectroscopy (TG-FTIR)

Thermogravimetric measurements may be performed using Netzsch Thermo-Microbalance TG 209 in combination with Bruker FTIR Spectrometer Vector 22 (sample tray with pinhole, N _{2 atmosphere of air} Heating rate 10 ℃/min).

The general method comprises the following steps:

as part of the study of the polymorphic form of compound (I), several crystallization experiments were performed. The experiments included different crystallization techniques such as suspension equilibration experiments, precipitation, cooling crystallization and vapor diffusion experiments.

Example 1: preparation of form A of Compound (I)

98mg of amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile was dissolved in 400. Mu.L of isopropyl acetate at room temperature. After stirring for one day, a very thick suspension was obtained. An additional 700 μ L of isopropyl acetate was added and after stirring for 2 hours the suspension was filtered (centrifuge cell filter, PTFE,0.22 μm) to obtain form a.

Example 2: preparation of form B of Compound (I) comprising 95% to 99% (E) -isomer

96mg of amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile is dissolved in 0.3mL of ethyl acetate. The solution obtained was inoculated with NaCl and stirred at room temperature. After stirring overnight, a cloudy solution was obtained and sonicated for 5 minutes. After stirring for an additional two days, a suspension was obtained and filtered (centrifugal cell filter, PTFE,0.22 μm) to obtain form B.

Example 3: alternative preparation of form B of compound (I) comprising 95% to 99% (E) -isomer

At Room Temperature (RT), 3.64g of amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile was dissolved in ethyl acetate (EtOAc) (11 mL) and the mixture of form a (20 mg) and form a and B (60 mg) was crystallized. The seed crystal is continuously present. The resulting slurry was stirred at RT for 3 days. Heptane (33 mL) was added dropwise (continuously) and the slurry was stirred at RT for 4 hours. The slurry was filtered and dried under vacuum at 30 ℃ for 16 hours to give 3.5g of form B (94% yield).

Example 4: alternative preparation of form B of compound (I) comprising >99% (E) -isomer

Form C of 430g of (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile (compound (I)) was combined with ethanol (4.1L) at about 15 ℃ to form a slurry. Form B seed (to about 5 wt.%) was then added and the slurry was stirred for about two days. The slurry was filtered and thermally dried under vacuum to obtain approximately 300g of compound (I) as form B (74% yield).

Example 5: preparation of form C of Compound (I)

100mg of amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile was combined with acetonitrile (MeCN) (0.5mL, 5vol). The solution was inoculated with form B of compound (I) and stirred at room temperature for 48 hours. After about 48 hours, a thick white, free-flowing slurry was obtained and identified as form C. Estimated yield: >50%.

Example 6: alternative preparation of form C of Compound (I) 1

A mixture of 61.2mg amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile with 49.8mg of forms a and B was suspended in 400 μ L of a mixture of acetonitrile/tert-butyl methyl ether (TBME) (1. After stirring for 10 minutes, the suspension was inoculated with form a. After stirring overnight at room temperature, an additional 400 μ Ι _ acetonitrile/TBME (1). After stirring at room temperature for 5 days, a very thick suspension was obtained and 600 μ L of acetonitrile/TBME (1. After a total of two weeks of stirring, the suspension was filtered (centrifugal unit filter, PTFE,0.22 μm) and the recovered solid was dried in air for about 1 hour to give form C.

Example 7: alternative preparation of form C of Compound (I) 2

9.3g of amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile was combined with MeCN (93mL, 10vol). The solution was seeded with form C (35 mg) and stirred at room temperature for 72h. Precipitation was observed after 2h. The solid was isolated by filtration and dried under vacuum at 30 ℃ for 1 hour to give form C. Yield: 76 percent.

Example 8: alternative preparation of form C of Compound (I) 3

100mg of amorphous (R) -2- [3- [ 4-amino-3- (2-fluoro-4-phenoxy-phenyl) pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carbonyl ] -4-methyl-4- [4- (oxetan-3-yl) piperazin-1-yl ] pent-2-enenitrile was combined with MeCN/MTBE (1.4 mL). The solution was seeded with form B seeds. And dissolving the seed crystal. The solution was then seeded with a mixture of seeds of forms a and B and stirred for 48 hours. No significant precipitation was observed. The solution was then seeded with form C seeds. Some thickening was observed. The solution was stirred for five days and the precipitate obtained by filtration was form C. Yield: 42 percent.

Example 9: single crystal X-ray diffraction

Compound (I) (10.2 mg) was dissolved with an internal solvent (acetonitrile) in a small vial, and then the small vial was placed in a larger bottle with an external solvent (isopropyl ether) and left to stand at 4 ℃ for 15 days to grow a single crystal. Using graphite-monochromatized MoK alpha

Single crystal X-ray diffraction data were collected on a Bruker D8Venture DUO diffractometer. The crystals were mounted on a MiTeGen MicroMount and collected using an Oxford Cryosystems 800 cryogenic apparatus at 200 (2) K. By the sum of

Data were collected by scanning and corrected for lorentz and polarization effects by using the APEX3 software suite and the WinGX publishing routine (farragia, 2005). All images were prepared using Ortep-3 for Windows.

The single crystal exhibits a P-1 space group having a triclinic system. The following unit cell dimensions were measured:

α＝93.654(3)°。

β＝104.400(3)°。

γ＝105.476(4)°。

Claims

1. a crystalline form A of Compound (I):

wherein C is a stereochemical centre.

2. Form a according to claim 1, characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2.

3. Form a according to claim 1 or 2, characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern of figure 1.

4. Form a according to any one of claims 1-3, characterized by a DSC thermogram with an endotherm (melting temperature) at about 146 ℃ to about 147 ℃.

5. Form A according to any one of claims 1-4, characterized by a DSC thermogram showing an onset of melting at about 140.6 ℃ to about 141.2 ℃.

6. Form A according to any one of claims 1 to 5, characterized by a mass loss between 25 ℃ and 200 ℃ of less than 1.0wt.% by thermogravimetric analysis.

7. Form A according to any one of claims 1 to 6, characterized by a water content of less than 1% when stored at 95% Relative Humidity (RH).

8. Form A according to any one of claims 1 to 7, wherein at least 95% of Compound (I) is the (E) isomer.

9. A crystalline form a of compound (I) prepared by a process comprising:

stirring the solution to form a precipitate; and

form a was isolated by filtration.

10. A crystalline form B of Compound (I):

wherein C is a stereochemical center.

11. Form B according to claim 10, characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.0 ± 0.2, and 22.9 ± 0.2.

12. Form B according to claim 10 or 11, wherein at least >99% of compound (I) is the (E) -isomer.

13. Form B according to claim 10 or 11, wherein 95% to 99% of compound (I) is the (E) -isomer.

14. Form B according to any one of claims 10-12, characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in figure 4B.

15. Form B according to any one of claims 10, 11 or 13, characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in figure 4A.

16. Form B according to any one of claims 10-12 or 14, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 144 ℃ to about 146 ℃.

17. Form B according to any one of claims 10-12, 14, or 16, characterized by a DSC thermogram showing an onset of melting at about 139.3 ℃.

18. Form B according to any one of claims 10, 11, 13, or 15, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 141 ℃ to about 142 ℃.

19. Form B according to any one of claims 10, 11, 13, 15, or 18, characterized by a DSC thermogram showing an onset of melting at about 131.8 ℃ to about 132.4 ℃.

20. Form B according to any one of claims 10-19, characterized by a water content of less than 1.3% when stored at 95% Relative Humidity (RH).

21. A crystalline form B of compound (I) prepared by a process comprising:

isolating form B by filtering the suspension.

22. A crystalline form B of compound (I) prepared by a process comprising:

isolating compound (I) in crystalline form B by filtration.

23. A crystalline form C of Compound (I):

wherein C is a stereochemical centre.

24. Form C according to claim 23, characterized by an X-ray powder diffraction pattern having signals at least three 2 Θ values selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2.

25. Form C according to claim 23 or 24, characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern of figure 7.

26. Form C according to any one of claims 23-25, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 118.5 ℃ to about 119 ℃, wherein the DSC scan rate is 15 ℃/min.

27. Form C according to any one of claims 23-26, characterized by a DSC thermogram showing an onset of melting at about 115.6 ℃ to about 116 ℃, wherein the DSC scan rate is 15 ℃/min.

28. Form C according to any one of claims 23-27, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 120.5 ℃ to about 121 ℃, wherein the DSC scan rate is 10 ℃/min.

29. Form C according to any one of claims 23-28, characterized by a DSC thermogram showing an onset of melting at about 118 ℃ to about 118.5 ℃, wherein the DSC scan rate is 10 ℃/min.

30. The crystalline form C according to any one of claims 23-29, wherein at least 95% of compound (I) is the (E) isomer.

31. The crystalline form C according to any one of claims 23-30, characterized by a P-1 space group.

32. Form C according to any one of claims 23-31, characterized by the following unit cell dimensions at 200 (2) K:

α＝93.654°

β＝104.400°

γ＝105.476°。

33. a crystalline form C of compound (I) prepared by a process comprising:

isolating form C by filtering the slurry.

34. A pharmaceutical composition comprising:

at least one crystalline form of compound (I) selected from the crystalline forms according to any one of claims 1-33; and

at least one pharmaceutically acceptable excipient.

35. The pharmaceutical composition of claim 34, wherein the pharmaceutical composition is in the form of a solid oral composition.

36. The pharmaceutical composition of claim 34 or 35, wherein the pharmaceutical composition is in the form of a tablet or capsule.

37. A method of inhibiting Bruton's Tyrosine Kinase (BTK) in a mammal, comprising administering to a mammal in need of said BTK inhibition a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1-33.

38. A method of treating a disease mediated by Bruton's Tyrosine Kinase (BTK) in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1-33.

39. A method of treating pemphigus vulgaris or pemphigus foliaceus in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1-33.

40. A method of treating immune thrombocytopenia in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1-33.

41. The method of any one of claims 37-40, wherein the mammal is a human.